Taxoids, preparation thereof and pharmaceutical compositions containing same

ABSTRACT

Novel taxoids of general formula (I), the preparation thereof and pharmaceutical compositions containing same, are disclosed. In general formula (I), Z is a hydrogen atom or a radical of general formula (H), wherein R 1  is an optionally substituted benzoyl radical or a radical R 2  --O--CO--, where R 2  is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, optionally substituted phenyl or heterocyclyl radical; R 3  is an alkyl, alkenyl, alkyl, cycloalkyl, phenyl, naphthyl or aromatic heterocyclic radical; R 4  is a hydroxy radical or an alkoxy, alkenyloxy, optionally substituted alkynyloxy, alkanoyloxy, alkenoyloxy, alkynyloxy, alkoxyacetyl or alkyloxycarbonyloxy radical, or a cycloalkyloxy, cycloalkenyloxy, arylcarbonyloxy or heterocyclylcarbonyloxy radical; and R 5  is an optionally substituted alkoxy radical or a cycloalkyloxy or cycloalkenyloxy radical. The novel compounds of general formula (I), wherein Z is a radical of general formula (II), have remarkable antitumoral and antineoplastic properties. ##STR1##

This application is a 371 of PCT/FR97/00386 dated Mar. 5, 1997.

The present invention relates to new taxoids of general formula:##STR2## in which

Z represents a hydrogen atom or a radical of general formula: ##STR3##in which:

R₁ represents a benzoyl radical optionally substituted with one or moreidentical or different atoms or radicals chosen from halogen atoms andalkyl radicals containing 1 to 4 carbon atoms, alkoxy radicalscontaining 1 to 4 carbon atoms or trifluoromethyl radicals, thenoyl orfuroyl radicals or a radical R₂ --O--CO-- in which R₂ represents:

an alkyl radical containing 1 to 8 carbon atoms, an alkenyl radicalcontaining 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, acycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkylradical containing 7 to 10 carbon atoms, these radicals being optionallysubstituted with one or more substituents chosen from halogen atoms andhydroxyl radicals, alkoxy radicals containing 1 to 4 carbon atoms,dialkylamino radicals in which each alkyl portion contains 1 to 4 carbonatoms, piperidino or morpholino radicals, 1-piperazinyl radicals(optionally substituted at the 4-position with an alkyl radicalcontaining 1 to 4 carbon atoms or with a phenylalkyl radical in whichthe alkyl portion contains 1 to 4 carbon atoms), cycloalkyl radicalscontaining 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6carbon atoms, phenyl radicals (optionally substituted with one or moreatoms or radicals chosen from halogen atoms and alkyl radicalscontaining 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4carbon atoms), cyano or carboxyl radicals or alkoxycarbonyl radicals inwhich the alkyl portion contains 1 to 4 carbon atoms,

a phenyl or α- or β-naphthyl radical optionally substituted with one ormore atoms or radicals chosen from halogen atoms and alkyl radicalscontaining 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4carbon atoms, or a 5-membered aromatic heterocyclic radical preferablychosen from furyl and thienyl radicals,

or a saturated heterocyclic radical containing 4 to 6 carbon atoms,optionally substituted with one or more alkyl radicals containing 1 to 4carbon atoms,

R₃ represents an unbranched or branched alkyl radical containing 1 to 8carbon atoms, an unbranched or branched alkenyl radical containing 2 to8 carbon atoms, an unbranched or branched alkynyl radical containing 2to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms,a phenyl or α- or β-naphthyl radical optionally substituted with one ormore atoms or radicals chosen from halogen atoms and alkyl, alkenyl,alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl,hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino,alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl,alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano,nitro and trifluoromethyl radicals, or a 5-membered aromatic heterocyclecontaining one or more identical or different hetero atoms chosen fromnitrogen, oxygen and sulphur atoms and optionally substituted with oneor more identical or different substituents chosen from halogen atomsand alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino,acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl,dialkylcarbamoyl or alkoxycarbonyl radicals, on the understanding that,in the substituents of the phenyl, α- or β-naphthyl and aromaticheterocyclic radicals, the alkyl radicals and the alkyl portions of theother radicals contain 1 to 4 carbon atoms, and that the alkenyl andalkynyl radicals contain 2 to 8 carbon atoms, and that the aryl radicalsare phenyl or α- or β-naphthyl radicals,

R₄ represents a hydroxyl radical or an alkoxy radical containing 1 to 6carbon atoms in an unbranched or branched chain, an alkenyloxy radicalcontaining 3 to 6 carbon atoms in an unbranched or branched chain, analkynyloxy radical containing 3 to 6 carbon atoms in an unbranched orbranched chain, a cycloalkyloxy radical containing 3 to 6 carbon atoms,a cycloalkenyloxy radical containing 3 to 6 carbon atoms, an alkanoyloxyradical in which the alkanoyl portion contains 2 to 6 carbon atoms in anunbranched or branched chain, an alkenoyloxy radical in which thealkenoyl portion contains 3 to 6 carbon atoms in an unbranched orbranched chain, an alkynoyloxy radical in which the alkynoyl portioncontains 3 to 6 carbon atoms in an unbranched or branched chain, analkoxyacetyl radical in which the alkyl portion contains 1 to 6 carbonatoms in an unbranched or branched chain, an alkylthioacetyl radical inwhich the alkyl portion contains 1 to 6 carbon atoms in an unbranched orbranched chain or an alkyloxycarbonyloxy radical in which the alkylportion contains 1 to 6 carbon atoms in an unbranched or branched chain,these radicals being optionally substituted with one or more halogenatoms or with an alkoxy radical containing 1 to 4 carbon atoms, analkylthio radical containing 1 to 4 carbon atoms or a carboxyl radical,an alkyloxycarbonyl radical in which the alkyl portion contains 1 to 4carbon atoms, a cyano or carbamoyl radical or an N-alkylcarbamoyl orN,N-dialkylcarbamoyl radical in which each alkyl portion contains 1 to 4carbon atoms or, with the nitrogen atom to which it is linked, forms asaturated 5- or 6-membered heterocyclic radical optionally containing asecond hetero atom chosen from oxygen, sulphur and nitrogen atoms,optionally substituted with an alkyl radical containing 1 to 4 carbonatoms or a phenyl radical or a phenylalkyl radical in which the alkylportion contains 1 to 4 carbon atoms, or alternatively R₄ represents acarbamoyloxy radical or an N-alkylcarbamoyloxy radical in which thealkyl portion contains 1 to 4 carbon atoms, an N,N-dialkylcarbamoyloxyradical in which each alkyl portion contains 1 to 4 carbon atoms or abenzoyloxy radical or a heterocyclylcarbonyloxy radical in which radicalthe heterocyclic portion represents a 5- or 6-membered aromaticheterocycle containing one or more hetero atoms chosen from oxygen,sulphur and nitrogen atoms,

R₅ represents an alkoxy radical containing 1 to 6 carbon atoms in anunbranched or branched chain optionally substituted with an alkoxyradical containing 1 to 4 carbon atoms, an alkenyloxy radical containing3 to 6 carbon atoms, an alkynyloxy radical containing 3 to 6 carbonatoms, a cycloalkyloxy radical containing 3 to 6 carbon atoms, acycloalkenyloxy radical containing 3 to 6 carbon atoms, these radicalsbeing optionally substituted with one or more halogen atoms or with analkoxy radical containing 1 to 4 carbon atoms, an alkylthio radicalcontaining 1 to 4 carbon atoms or a carboxyl radical, analkyloxycarbonyl radical in which the alkyl portion contains 1 to 4carbon atoms, a cyano or carbamoyl radical or an N-alkylcarbamoyl orN,N-dialkylcarbamoyl radical in which each alkyl portion contains 1 to 4carbon atoms or, with the nitrogen atom to which it is linked, forms asaturated 5- or 6-membered heterocyclic radical optionally containing asecond hetero atom chosen from oxygen, sulphur and nitrogen atoms,optionally substituted with an alkyl radical containing 1 to 4 carbonatoms or a phenyl radical or a phenylalkyl radical in which the alkylportion contains 1 to 4 carbon atoms.

Preferably, the aryl radicals which can be represented by R₃ are phenylor α- or β-naphthyl radicals optionally substituted with one or moreatoms or radicals chosen from halogen atoms (fluorine, chlorine,bromine, iodine) and alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy,alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl,acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino,dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl,cyano, nitro and trifluoromethyl radicals, on the understanding that thealkyl radicals and the alkyl portions of the other radicals contain 1 to4 carbon atoms, that the alkenyl and alkynyl radicals contain 2 to 8carbon atoms and that the aryl radicals are phenyl or α- or β-naphthylradicals.

Preferably, the heterocyclic radicals which can be represented by R₃ are5-membered aromatic heterocyclic radicals containing one or moreidentical or different atoms chosen from nitrogen, oxygen and sulphuratoms, optionally substituted with one or more identical or differentsubstituents chosen from halogen atoms (fluorine, chlorine, bromine,iodine) and alkyl radicals containing 1 to 4 carbon atoms, aryl radicalscontaining 6 to 10 carbon atoms, alkoxy radicals containing 1 to 4carbon atoms, aryloxy radicals containing 6 to 10 carbon atoms, aminoradicals, alkylamino radicals containing 1 to 4 carbon atoms,dialkylamino radicals in which each alkyl portion contains 1 to 4 carbonatoms, acylamino radicals in which the acyl portion contains 1 to 4carbon atoms, alkoxycarbonylamino radicals containing 1 to 4 carbonatoms, acyl radicals containing 1 to 4 carbon atoms, arylcarbonylradicals in which the aryl portion contains 6 to 10 carbon atoms, cyano,carboxyl or carbamoyl radicals, alkylcarbamoyl radicals in which thealkyl portion contains 1 to 4 carbon atoms, dialkylcarbamoyl radicals inwhich each alkyl portion contains 1 to 4 carbon atoms or alkoxycarbonylradicals in which the alkoxy portion contains 1 to 4 carbon atoms.

Preferably, the radical R₄ represents a hydroxyl radical or anunbranched or branched alkoxy radical containing 1 to 6 carbon atoms oran alkanoyloxy radical containing 2 to 6 carbon atoms optionallysubstituted with a methoxy, ethoxy, methylthio, ethylthio, carboxyl,methoxycarbonyl, ethoxycarbonyl, cyano, carbamoyl, N-methylcarbamoyl,N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,N-pyrrolidinocarbonyl or N-piperidinocarbonyl and R₅ represents anunbranched or branched alkoxy radical containing 1 to 6 carbon atoms.

More especially, the present invention relates to the products ofgeneral formula (I) in which Z represents a hydrogen atom or a radicalof general formula (II) in which R₁ represents a benzoyl radical or aradical R₂ --O--CO-- in which R₂ represents a tert-butyl radical and R₃represents an alkyl radical containing 1 to 6 carbon atoms, an alkenylradical containing 2 to 6 carbon atoms, a cycloalkyl radical containing3 to 6 carbon atoms, a phenyl radical optionally substituted with one ormore identical or different atoms or radicals chosen from halogen atoms(fluorine, chlorine) and alkyl (methyl), alkoxy (methoxy), dialkylamino(dimethylamino), acylamino (acetylamino), alkoxycarbonylamino(tert-butoxycarbonylamino) and trifluoromethyl radicals, or a 2- or3-furyl, 2- or 3-thienyl or 2-, 4- or 5-thiazolyl radical, and R₄represents a hydroxyl radical or an unbranched or branched alkyloxyradical containing 1 to 6 carbon atoms or an alkanoyloxy radicalcontaining 2 to 6 carbon atoms and R₅ represents an unbranched orbranched alkyloxy radical containing 1 to 6 carbon atoms.

Still more especially, the present invention relates to the products ofgeneral formula (I) in which Z represents a hydrogen atom or a radicalof general formula (II) in which R₁ represents a benzoyl radical or aradical R₂ --O--CO-- in which R₂ represents a tert-butyl radical and R₃represents an isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or5-thiazolyl radical, R₄ represents a hydroxyl radical or a methoxy,ethoxy or propoxy radical and R₅ represents a methoxy radical.

The products of general formula (I) in which Z represents a radical ofgeneral formula (II) display noteworthy antitumour and antileukaemicproperties.

According to the present invention, the new products of general formula(I) in which Z represents a radical of general formula (II) may beobtained by esterification of a product of general formula: ##STR4## inwhich R₄ and R₅ are defined as above, by means of an acid of generalformula: ##STR5## in which R₁ and R₃ are defined as above, and either R₆represents a hydrogen atom and R₇ represents a group protecting thehydroxyl function, or R₆ and R₇ together form a saturated 5- or6-membered heterocycle, or of a derivative of this acid, to obtain anester of general formula: ##STR6## in which R₁, R₃, R₄, R₅, R₆ and R₇are defined as above, followed by the replacement of the protectivegroups represented by R₇ and/or R₆ and R₇ with hydrogen atoms.

To obtain a product of general formula (I) in which R₄ represents ahydroxyl radical, it is advantageous to protect the hydroxyl function atthe 10-position of the product of general formula (III), prior to theesterification, in the form, for example, of an alkoxyacetoxy radicaland then to replace the protective group at the 10-position with ahydroxyl radical by means, for example, of hydrazine hydrate and theprotective groups R₇ and/or R₆ and R₇ with hydrogen atoms.

The esterification by means of an acid of general formula (IV) may becarried out in the presence of a condensing agent (reactive carbonate,carbodiimide) and of an activating agent (aminopyridines) in an organicsolvent (ether, ester, ketones, nitrites, aliphatic hydrocarbons,halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at atemperature of between -10 and 90° C.

The esterification may also be performed using the acid of generalformula (IV) in the form of a symmetric anhydride, working in thepresence of an activating agent (aminopyridines), in an organic solvent(ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenatedaliphatic hydrocarbons, aromatic hydrocarbons) at a temperature ofbetween 0 and 90° C.

The esterification may also be performed using the acid of generalformula (IV) in the form of a halide or in the form of a mixed anhydridewith an aliphatic or aromatic acid, optionally prepared in situ, in thepresence of a base (tertiary aliphatic amine), working in an organicsolvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons,halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at atemperature of between 0 and 80° C.

Preferably, R₆ represents a hydrogen atom and R₇ represents a groupprotecting the hydroxyl function or R₆ and R₇ together form a saturated5- or 6-membered heterocycle.

When R₆ represents a hydrogen atom, R₇ preferably represents amethoxymethyl, 1-ethoxyethyl, benzoyloxymethyl, trimethylsilyl,triethylsilyl, β-trimethylsilylethoxymethyl, benzoyloxycarbonyl ortetrahydropyranyl radical.

When R₆ and R₇ together form a heterocycle, the latter is preferably anoxazolidine ring optionally mono-substituted or gem-disubstituted at the2-position.

The replacement of the protective groups R₇ and/or R₆ and R₇ withhydrogen atoms may be carried out, depending on their nature, in thefollowing manner:

1) When R₆ represents a hydrogen atom and R₇ represents a groupprotecting the hydroxyl function, the replacement of the protectivegroups with hydrogen atoms is carried out by means of an inorganic acid(hydrochloric acid, sulphuric acid, hydrofluoric acid) or an organicacid (acetic acid, methanesulphonic acid, trifluoromethanesulphonicacid, p-toluenesulphonic acid), used alone or in the form of a mixture,working in an organic solvent chosen from alcohols, ethers, esters,aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatichydrocarbons and nitrites, at a temperature of between -10 and 60° C.,or by means of a source of fluoride ions such as a hydrofluoricacid-triethylamine complex or by catalytic hydrogenation,

2) When R₆ and R₇ together form a saturated 5- or 6-membered heterocycleand more particularly an oxazolidine ring of general formula: ##STR7##in which R₁ is defined as above, R₈ and R₉, which are identical ordifferent, represent a hydrogen atom or an alkyl radical containing 1 to4 carbon atoms, or an aralkyl radical in which the alkyl portioncontains 1 to 4 carbon atoms and the aryl portion preferably representsa phenyl radical optionally substituted with one or more alkoxy radicalscontaining 1 to 4 carbon atoms, or an aryl radical preferablyrepresenting a phenyl radical optionally substituted with one or morealkoxy radicals containing 1 to 4 carbon atoms, either R₈ represents analkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radicalsuch as trichloromethyl or a phenyl radical substituted with atrihalomethyl radical such as trichloromethyl and R₉ represents ahydrogen atom, or R₈ and R₉ together form, with the carbon atom to whichthey are linked, a ring having 4 to 7 members, the replacement of theprotective group formed by R₆ and R₇ with hydrogen atoms may be carriedout, according to the meanings of R₁, R₈ and R₉, in the followingmanner:

a) When R₁ represents a tert-butoxycarbonyl radical, R₈ and R₉, whichare identical or different, represent an alkyl radical or an aralkyl(benzyl) or aryl (phenyl) radical, either R₈ represents a trihalomethylradical or a phenyl radical substituted with a trihalomethyl radical,and R₉ represents a hydrogen atom, or R₈ and R₉ together form a 4- to7-membered ring, the treatment of the ester of general formula (V) withan inorganic or organic acid, optionally in an organic solvent such asan alcohol, gives the product of general formula: ##STR8## in which R₃,R₄ and R₅ are defined as above, which is acylated by means of benzoylchloride in which the phenyl ring is optionally substituted, thenoylchloride, furoyl chloride or a product of general formula:

    R.sub.2 --O--CO--X                                         (VIII)

in which R₂ is defined as above and X represents a halogen atom(fluorine, chlorine) or a residue --O--R₂ or --O--CO--O--R₂, to obtain aproduct of general formula (I) in which Z represents a radical ofgeneral formula (II).

Preferably, the product of general formula (V) is treated with formicacid at a temperature in the region of 20° C., to give the product ofgeneral formula (VII).

Preferably, the acylation of the product of general formula (VII) bymeans of benzoyl chloride in which the phenyl radical is optionallysubstituted, thenoyl chloride or furoyl chloride or a product of generalformula (VIII) is carried out in an inert organic solvent chosen fromesters such as ethyl acetate, isopropyl acetate or n-butylacetate andhalogenated aliphatic hydrocarbons such as dichloromethane or1,2-dichloroethane in the presence of an inorganic base such as sodiumbicarbonate or an organic base such as triethylamine. The reaction iscarried out at a temperature of between 0 and 50° C., preferably in theregion of 20° C.

b) When R₁ represents an optionally substituted benzoyl radical, athenoyl or furoyl radical or a radical R₂ O--CO-- in which R₂ is definedas above, R₈ represents a hydrogen atom or an alkoxy radical containing1 to 4 carbon atoms or a phenyl radical substituted with one or morealkoxy radicals containing 1 to 4 carbon atoms and R₉ represents ahydrogen atom, the replacement of the protective group formed by R₆ andR₇ with hydrogen atoms is carried out in the presence of an inorganicacid (hydrochloric acid, sulphuric acid) or an organic acid (aceticacid, methanesulphonic acid, trifluoromethanesulphonic acid,p-toluenesulphonic acid), used alone or in the form of a mixture, in astoichiometric or catalytic quantity, working in an organic solventchosen from alcohols, ethers, esters, aliphatic hydrocarbons,halogenated aliphatic hydrocarbons and aromatic hydrocarbons at atemperature of between -10 and 60° C., preferably between 15 and 30° C.

According to the invention, the products of general formula (I) in whichR₄ and R₅ are defined as above, R4 not being capable of represents ahydroxyl radical and Z represents a hydrogen atom or a radical ofgeneral formula (II) may be obtained by the action of a product ofgeneral formula:

    R'.sub.4 --X.sub.1                                         (IX)

in which R'₄ is such that R'₄ --O is identical to R₄ defined as aboveand X₁ represents a halogen atom, on a product of general formula:##STR9## in which R₅ is defined as above and Z₁ represents a hydrogenatom or a group protecting the hydroxyl function or a radical of generalformula: ##STR10## in which R₁, R₃, R₆ and R₇ are defined as above,optionally followed by the replacement of the protective groups withhydrogen atoms.

Generally, the action of the product of general formula (IX) on aproduct of general formula (X) is carried out, after metalation of thehydroxyl function at the 10-position by means of an alkali metal hydridesuch as sodium hydride, an alkali metal amide such as lithium amide oran alkali metal alkylide such as butyllithium, working in an organicsolvent such as dimethylformamide or tetrahydrofuran, at a temperatureof between 0 and 50° C.

When Z₁ represents a group protecting the hydroxyl function, this groupis preferably a silylated radical, such as a trialkylsilyl radical,whose replacement with a hydrogen atom is carried out by means of anacid such as hydrofluoric acid or trifluoroacetic acid, in the presenceof a base such as triethylamine or pyridine optionally substituted withone or more alkyl radicals containing 1 to 4 carbon atoms, optionallycombined with an inert organic solvent such as a nitrile such asacetonitrile or a halogenated aliphatic hydrocarbon such asdichloromethane, at a temperature of between 0 and 80° C.

When Z₁ represents a radical of general formula (XI), the replacement ofthe protective groups R₆ and/or R₆ and R₇ with hydrogen atoms is carriedout under the conditions described above for the replacement of theprotective groups of the product of general formula (V).

The product of general formula (X) may be obtained by reduction of aproduct of general formula: ##STR11## in which R₅ and R₁ are defined asabove.

Generally, the reducing agent is chosen from aluminohydrides orborohydrides such as alkali or alkaline-earth metal borohydrides such assodium borohydride, in the presence of an aliphatic alcohol containing 1to 4 carbon atoms such as methanol, the reduction being performed at atemperature of between 0° and 50° C., preferably in the region of 20° C.

The product of general formula (XII) may be obtained by the action of anoxidizing agent on a product of general formula: ##STR12## in which R₅and Z₁ are defined as above.

Generally, the oxidizing agent is chosen from agents which make itpossible to oxidize the secondary alcohol function without affecting therest of the molecule, such as for example oxygen, ammonium perruthenate,manganese dioxide, copper acetate or pyridinium chlorochromate, workingin an organic solvent such as optionally halogenated aliphatichydrocarbons such as dichloromethane, at a temperature of between 0 and50° C., preferably in the region of 25° C.

The product of general formula (XIII) may be obtained by the action ofhydrazine, preferably in hydrate form, on a product of general formula:##STR13## in which Z₁ and R₅ are defined as above and R"₄ represents analkoxyacetoxy or alkylthioacetoxy radical in which the alkyl portioncontains 1 to 4 carbon atoms.

Generally, the reaction is carried out working in an aliphatic alcoholcontaining 1 to 4 carbon atoms such as ethanol, at a temperature ofbetween 0 and 50° C.

The product of general formula (XIV) may be obtained by the action ofactivated Raney nickel, in the presence of an aliphatic alcoholcontaining 1 to 3 carbon atoms, on a product of general formula:##STR14## in which Z₁ and R"₄ are defined as above, R' and R", which areidentical or different, represent a hydrogen atom or an alkyl radicalcontaining 1 to 6 carbon atoms, an alkenyl radical containing 2 to 6carbon atoms, an alkynyl radical containing 2 to 6 carbon atoms, acycloalkyl radical containing 3 to 6 carbon atoms or a cycloalkenylradical containing 3 to 6 carbon atoms, or R' and R" together form, withthe carbon atom to which they are linked, a cycloalkyl radicalcontaining 3 to 6 carbon atoms or a cycloalkenyl radical containing 4 to6 carbon atoms.

Generally, the action of the activated Raney nickel in the presence ofthe aliphatic alcohol is carried out at a temperature of between -10 and60° C.

The product of general formula (XV) may be obtained by the action of adialkyl sulphoxide of general formula: ##STR15## in which R' and R" aredefined as above, on a product of general formula: ##STR16## in which Z₁and R"₄ are defined as above.

Generally, the reaction of the sulphoxide of general formula (XVI),preferably dimethyl sulphoxide, on the product of general formula (XVII)is carried out in the presence of a mixture of acetic acid and aceticanhydride or of a derivative of acetic acid such as a haloacetic acid,at a temperature of between 0 and 50° C., preferably in the region of25° C.

The product of general formula (XVII) may be obtained by the action, forexample, of a triethylamine-hydrofluoric acid complex, on a product ofgeneral formula: ##STR17## in which Z₁ and R"₄ are defined as above.

Generally, the reaction is carried out working in an organic solventsuch as an optionally halogenated aliphatic hydrocarbon, at atemperature of between -25 and 25° C.

The product of general formula (XVIII) may be obtained under theconditions described in international patent PCT WO 95/11241.

The new products of general formula (I) obtained by carrying out theprocesses according to the invention may be purified according to knownmethods such as crystallization or chromatography.

The products of general formula (I) in which Z represents a radical ofgeneral formula (II) display noteworthy biological properties.

In vitro, measurement of the biological activity is performed on tubulinextracted from pig's brain by the method of M. L. Shelanski et al.,Proc. Natl. Acad. Sci. USA, 70, 765-768 (1973). Study of thedepolymerization of microtubules into tubulin is performed according tothe method of G. Chauviere et al., C. R. Acad. Sci., 293, series II,501-503 (1981). In this study, the products of general formula (I) inwhich Z represents a radical of general formula (II) were shown to be atleast as active as Taxol and Taxotere.

In vivo, the products of general formula (I) in which Z represents aradical of general formula (II) were shown to be active in mice graftedwith B16 melanoma at doses of between 1 and 10 mg/kg administeredintraperitoneally, as well as on other liquid or solid tumours.

The new products have antitumour properties, and more especiallyactivity against tumours which are resistant to Taxol® or to Taxotere®.Such tumours comprise colon tumours which have a high expression of themdr 1 gene (multiple drug resistance gene). Multiple drug resistance isa customary term relating to the resistance of a tumour to differentproducts having different structures and mechanisms of action. Taxoidsare generally known to be strongly recognized by experimental tumourssuch as P388/DOX, a cell line selected for its resistance to doxorubicin(DOX) which expresses mdr 1.

The example which follows illustrates the present invention.

EXAMPLE 1

35 mg of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10α-dihydroxy-7β-methoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylateis dissolved in 0.74 cm³ of a 0.1N hydrochloric acid ethanolic solutioncontaining 1% of water. The solution thus obtained was stirred for 2hours at a temperature in the region of 20° C. and then supplementedwith 1 cm³ of a saturated aqueous sodium hydrogen carbonate solution and3 cm³ of dichloromethane. The mixture was stirred for 5 minutes at atemperature in the region of 20° C. and separated by decantation of theorganic phase. The aqueous phase was reextracted two times with 3 cm³ ofdichloromethane. The organic phases were pooled, dried over magnesiumsulphate, filtered and concentrated to dryness under reduced pressure(2.7 kPa) at 40° C. 34 mg of a white foam were obtained which werepurified by chromatography on silica gel plates [(gel 1 mm thick, 1plate of 20×20 cm, eluent, dichloromethane/methanol (95-5 by volume)].After locating, using UV rays, the zone corresponding to the desiredproduct adsorbed, this zone was scraped off and the silica recovered waswashed on sintered glass 10 times with 2 cm³ of ethyl acetate. Thefiltrates were pooled and concentrated to dryness 5 under reducedpressure (2.7 kPa) at 20° C. 22 mg of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10α-dihydroxy-7β-methoxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate werethereby obtained in the form of a white foam, the characteristics ofwhich were as follows:

--¹ H NMR spectrum (400 MHz; CDCl₃ ; chemical shifts δ in ppm; couplingconstants J in Hz):1.13 (s, 3H:--CH₃ at position 16 or 17); 1.27 (s,3H:--CH₃ at position 16 or 17); 1.38 [s, 9H:--C(CH₃)₃ ]; 1.72 (s,3H:--CH₃); 1.76 (s, 1H:OH at position 1); 1.82 and 2.75 (2 mts, 1Heach:--CH₂ -- at position 6); 2.08 (s, 3H:--CH₃); 2.28 and 2.35 (2 dd,J=16 and 9, 1H each:--CH₂ -- at position 14; 2.40 (s, 3H:--COCH₃); 2.71(d, J=2, 1H:--OH at position 10); 3.30 (s, 3H:--OCH₃); 3.42 (broad s,1H:--OH at position 2'); 4.20 and 4.32 (2 d, J=8.5, 1H each:--CH₂ -- atposition 20); 4.27 (d, J=7.5, 1H:--H at position 3); 4.31 (mt, 1H:--H atposition 7); 4.64 (mt, 1H:--H at position 2'); 5.02 (broad d, J=10, 1H:--H at position 5); 5.21 (mt, 1H:--H at position 10); 5.32 (broad d,J=10, 1H:--H at position 3'); 5.48 (d, J=10, 1H:--CONH--); 5.65 (d,J=7.5, 1H:--H at position 2); 6.18 (broad t, J=9, 1H:--H at position13); from 7.25 to 7.45 (mt, 5H:--C₆ H₅ at position 3'); 7.52 [t, J=7.5,2H:--OCOC₆ H₅ (--H at position 3 and H at position 5)]; 7.63 [t, J=7.5,1H:--OCOC₆ H₅ (--H at position 4)]; 8.13 [d, J=7.5, 2H:--OCOC₆ H₅ (--Hat position 2 and H at position 6)].

4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10α-dihydroxy-7β-methoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatemay be prepared in the following manner:

9 mg of sodium tetrahydruroborate were added, at a temperature in theregion of 20° C., to a solution of 45 mg of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7.beta.-methoxy-9,10-dioxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatein 2 cm³ of anhydrous ethanol, maintained under an argon atmosphere andwith stirring, and the reaction mixture was maintained stirring for 1hour at a temperature in the region of 20° C. and then 1 cm³ ofdistilled water was added and the mixture was stirred for 5 minutes at20° C. 3 cm³ of dichloromethane were added and the organic phase wasseparated by decantation. The aqueous phase was reextracted with twice 3cm³ of dichloromethane. The organic phases were pooled, dried overmagnesium sulphate, filtered on sintered glass and concentrated todryness under reduced pressure (2.7 kPa) at 40° C. A white foam wasobtained which is purified by chromatography on a silica gel plate [(gel1 mm thick, 1 plate of 20×20 cm, eluent: dichloromethane/methanol (95-5by volume)]. After locating, using UV rays, the zone corresponding tothe desired product adsorbed, this zone was scraped off and the silicarecovered is washed on sintered glass 10 times with 2 cm³ of ethylacetate. The filtrates were pooled and concentrated to dryness underreduced pressure (2.7 kPa) at 20° C. 22.5 mg of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10α-dihydroxy-7β-methoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylateare thereby obtained in the form of a white foam.

4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7.beta.-methoxy-9,10-dioxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatewere be prepared in the following manner:

500 mg of a 4 Å molecular sieve powder and 43 mg of pyridiniumchlorochromate were successively added, at a temperature in the regionof 20° C., to a solution of 100 mg of 4α-acetoxy-2α-benzoyloxy5β,20-epoxy-1β,10β-dihydroxy-7β-methoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatein 5 cm³ of dichloromethane, maintained under an argon atmosphere andwith stirring. The suspension obtained was stirred for 21 hours at atemperature in the region of 20° C. and then filtered on sintered glasscoated with celite. The sintered glass was washed 3 times with 5 cm³ ofdichloromethane. The filtrates were pooled and supplemented withpowdered animal charcoal and then filtered on sintered glass andconcentrated to dryness under reduced pressure (2.7 kPa) at 40° C. Ayellow foam was thereby obtained which is purified by chromatography ona silica gel plate [(gel 1 mm thick, 1 plate of 20×20 cm, eluent:dichloromethane/methanol (95-5 by volume)]. After locating, using UVrays, the zone corresponding to the desired product adsorbed, this zonewas scraped off and the silica recovered was washed on sintered glass 10times with 5 cm³ of ethyl acetate. The filtrates were pooled andconcentrated to dryness under reduced pressure (2.7 kPa) at 20° C. 47 mgof4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7.beta.-methoxy-9,10-dioxo-11-taxen-13α-yl(2R,4S, 5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatewere thereby obtained in the form of a light beige foam.

4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-7β-methoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatewere prepared in the following manner:

0.263 cm³ of hydrazine monohydrate was added dropwise, and at atemperature in the region of 20° C., to a solution of 150 mg of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7.beta.-methoxy-10β-methoxyacetoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatein 4 cm³ of anhydrous ethanol, maintained under an argon atmosphere andwith stirring. The reaction medium was maintained stirring for 1 hour ata temperature in the region of 20° C. and then poured into a mixture of100 cm³ of ethyl acetate and 50 cm³ of distilled water. The organicphase was separated by decantation and the aqueous phase was reextracted2 times with 50 cm³ of ethyl acetate. The organic phases were pooled,washed 4 times with 50 cm³ of distilled water, dried over magnesiumsulphate, filtered and concentrated to dryness under reduced pressure(2.7 kPa) at 40° C. 180 mg of a white foam were obtained which werepurified by chromatography on silica gel plates [gel 1 mm thick, 20×20cm plates, eluent: dichloromethane/ethanol (90-10 by volume)] in 90-mgfractions (2 plates). After locating, using UV rays, the zonecorresponding to the desired product adsorbed, this zone was scraped offand the silica recovered was washed on sintered glass 10 times with 10cm³ of ethyl acetate. The filtrates were pooled and concentrated todryness under reduced pressure (2.7 kPa) at 40° C. 113 mg of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-7β-methoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatewere thereby obtained in the form of a white foam.

4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7.beta.-methoxy-10β-methoxyacetoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatewere prepared in the following manner:

100 cm³ of an ethanolic suspension of activated Raney nickel (obtainedfrom 80 cm³ of an aqueous commercial suspension at about 50%, bysuccessive washes, up to a pH in the region of 7, with 15 times 100 cm³of distilled water and 4 times with 150 cm³ of ethanol) were added, at atemperature in the region of 20° C., to a solution of 1.041 g of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-10.beta.-methoxyacetoxy-7β-methylthiomethoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatein 100 cm³ of anhydrous ethanol, maintained under an argon atmosphereand with stirring. The reaction medium was maintained stirring for 7days at a temperature in the region of 20° C. and then filtered onsintered glass. The sintered glass was washed 3 times with 100 cm³ ofethanol, the filtrates were pooled and concentrated to dryness underreduced pressure (2.7 kPa) at 40° C. 821 mg of a white foam wereobtained which are purified by chromatography on 75 g of silica(0.063-0.2 mm) contained in a column 2.5 cm in diameter [eluent:dichloromethane/ethyl acetate (90-10 by volume)], collecting 5-cm³fractions. The fractions containing only the desired product were pooledand concentrated to dryness under reduced pressure (2.7 kPa) at 40° C.228 mg of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7.beta.-methoxy-10β-methoxyacetoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatewere thereby obtained in the form of a white foam.

4α-acetoxy-2α-benzoyloxy-5,20-epoxy-1β-hydroxy-10β-methoxyacetoxy-7β-methylthiomethoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatewere prepared in the following manner:

3.35 cm³ of acetic acid and 11.5 cm³ of acetic anhydride were added, ata temperature in the region of 20° C., to a solution of 5 g of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β-dihydroxy-10β-methoxyacetoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatein 165 cm³ of anhydrous dimethyl sulphoxide, maintained under an argonatmosphere and with stirring. The reaction medium was maintainedstirring for 3 days at a temperature in the region of 20° C. and thenpoured into 500 cm³ of dichloromethane. 100 cm³ of a saturated aqueouspotassium carbonate solution were then added, with vigorous stirring,until a pH in the region of 7 was obtained. After stirring for 10minutes, the organic phase was separated by decantation and the aqueousphase was reextracted 2 times with 250 cm³ of dichloromethane. Theorganic phases were pooled, washed 3 times with 100 cm³ of distilledwater, dried over magnesium sulphate, filtered and concentrated todryness under reduced pressure (2.7 kPa) at 40° C. 9.5 g of a paleyellow oil were obtained which were purified by chromatography on 250 gof silica (0.063-0.4 mm) contained in a column 3 cm in diameter [eluent:dichloromethane/methanol (99-1 by volume)], collecting 50-cm³ fractions.The fractions containing only the desired product were pooled andconcentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 3.01g of4α-acetoxy-2α-benzoyloxy-5↑,20-epoxy-1β-hydroxy-10.beta.-methoxyacetoxy-7β-methylthiomethoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatewere thereby obtained in the form of a white foam.

4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β-dihydroxy-10β-methoxyacetoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatewere prepared in the following manner:

220 cm³ of the triethylamine-hydrofluoric acid complex (1-3 by mol) wereadded dropwise, at a temperature in the region of 0° C., to a solutionof 20 g of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-7β-triethylsilyloxy-15-hydroxy-10β-methoxyacetoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatein 200 cm³ of anhydrous dichloromethane, maintained under an argonatmosphere and with stirring. The reaction medium was then heated up toa temperature in the region of 20° C., maintained for 3 hours at thistemperature and poured into 4 liters of an aqueous saturated sodiumhydrogen carbonate solution. The pH of the reaction medium was thusbrought to about 7. After stirring for 10 minutes, the organic phase wasseparated by decantation and the aqueous phase was extracted 2 timeswith 100 cm³ of dichloromethane. The organic phases were pooled, washedwith 100 cm³ of distilled water, dried over magnesium sulphate, filteredand concentrated to dryness under reduced pressure (2.7 kPa) at 40° C.17.4 g of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β-dihydroxy-10β-methoxyacetoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatewere thereby obtained in the form of a white foam.

4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-7β-triethylsilyloxy-1β-hydroxy-10β-methoxyacetoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatewere prepared under the conditions described in internationalapplication PCT WO 95/11241.

EXAMPLE 2

A solution of 40 mg of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7.beta.,10α-dimethoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatein 0.84 cm³ of a 0.1N hydrochloric acid ethanolic solution containing 1%water was stirred for 2 hours at a temperature in the region of 20° C.and then supplemented with 1 cm³ of a saturated aqueous sodium hydrogencarbonate solution and with 2 cm³ of dichloromethane. The mixture wasstirred for 5 minutes at a temperature in the region of 20° C. and theorganic phase was separated by decantation. The aqueous phase isreextracted 2 time with 2 cm³ of dichloromethane. The organic phaseswere pooled, dried over magnesium sulphate, filtered and concentrated todryness under reduced pressure (2.7 kPa) at 40° C. 38 mg of a white foamwere obtained which are purified by chromatography on a silica gel plate[gel 1 mm thick, 1 plate of 20×20 cm, eluent: dichloromethane/methanol(95-5 by volume)]. After locating, using UV rays, the zone correspondingto the desired product adsorbed, this zone was scraped off and thesilica recovered was washed on sintered glass 10 times with 2 cm³ ofethyl acetate. The filtrates were pooled and concentrated to drynessunder reduced pressure (2.7 kPa) at 20° C. 14 mg of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7.beta.,10α-dimethoxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate werethereby obtained in the form of a white foam, the characteristics ofwhich were as follows: --¹ H NMR spectrum (400 MHz; CDCl₃ ; chemicalshifts δ in ppm; coupling constants J in Hz): 1.13 (s, 3H:--CH₃ atposition 16 or 1 at position 7); 1.27 (s, 3H:--CH₃ at position 16 or17); 1.39 [s, 9H:--C(CH₃)₃ ]; 1.72 (s, 3H:--CH₃); 1.76 (s, 1H:--OH atposition 1); 1.78 and 2.78 (2 mts, 1H each:--CH₂ -- at position 6); 2.03(s, 3H:--CH₃); 2.27 and 2.37 (2dd, J=16 and 9, 1H each:--CH₂ -- atposition 14); 2.38 (s, 3H:--COCH₃); 3.28 (s, 3H:--OCH₃); 3.42 (broad s,1H:--OH at position 2'); 3.47 (s, 3H:--OCH₃); from 4.15 to 4.25 (mt,2H:--H at position 3 and --H at position 7); 4.18 and 4.32 (2 d, J=8.5,1H each:--CH₂ -- at position 20); 4.52 (broad s, 1H:--H at position 10);4.64 (mt, 1H:--H at position 2'); 5.01 (broad d, J=10, 1H:--H atposition 5); 5.30 (broad d, J=10, 1H:--H at position 3'); 5.45 (d, J=10,1H:--CONH--); 5.65 (d, J=7.5, 1H:--H at position 2); 6.15 (broad t, J=9,1H:--H at position 13); from 7.25 to 7.45 (mt, 5H:--C₆ H₅ at position3'); 7.51 [t, J=7.5, 2H:--OCOC₆ H₅ (--H at position 3 and H at position5)]; 7.62 [t, J=7.5, 1H:--OCOC₆ H₅ (--H at position 4)]; 8.12 [d, J=7.5,2H:--OCOC₆ H₅ (--H at position 2 and H at position 6)].

4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7.beta.,10α-dimethoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatemay be prepared in the following manner:

0.5 cm³ of methyl iodide and 3.6 mg of a dispersion at 50% by weight ofsodium hydride in mineral oil were added, at a temperature in the regionof 0° C., to a solution of 37 mg of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10α-dihydroxy-7β-methoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatein 0.5 cm³ of anhydrous dimethylformamide, maintained under an argonatmosphere and with stirring. The reaction medium was maintainedstirring for 30 minutes at a temperature in the region of OOC and then10 cm³ of ethyl acetate and 5 cm³ of an aqueous saturated ammoniumchloride solution were added. After stirring for 5 minutes, the organicphase was separated by decantation and the aqueous phase was reextracted2times with 5 cm³ of ethyl acetate. The organic phases were pooled,washed 2 times with 10 cm³ of distilled water, dried over magnesiumsulphate, filtered and concentrated to dryness under reduced pressure(2.7 kPa) at 40° C. A white foam was obtained which was purified bychromatography on a silica gel plate [gel 1 mm thick, 1 plate of 20×20cm, eluent: dichloromethane/methanol (95-5 by volume)]. After locating,using UV rays, the zone corresponding to the desired product adsorbed,this zone was scraped off and the silica recovered was washed onsintered glass 10 times with 2 cm³ of ethyl acetate. The filtrates werepooled and concentrated to dryness under reduced pressure (2.7 kPa) at20° C. 26 mg of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7.beta.,10α-dimethoxy-9-oxo-11-taxen-13α-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylatewere thereby obtained in the form of a white foam.

The new products of general formula (I) in which Z represents a radicalof general formula (II) manifest significant inhibitory activity withrespect to abnormal cell proliferation, and possess therapeuticproperties permitting the treatment of patients having pathologicalconditions associated with abnormal cell proliferation. The pathologicalconditions include the abnormal cell proliferation of malignant ornon-malignant cells of various tissues and/or organs, comprising,without implied limitation, muscle, bone or connective tissue, the skin,brain, lungs, sex organs, the lymphatic or renal systems, mammary orblood cells, liver, the digestive system, pancreas and thyroid oradrenal glands. These pathological conditions can also includepsoriasis, solid tumours, cancers of the ovary, breast, brain, prostate,colon, stomach, kidney or testicles, Kaposi's sarcoma,cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms' tumour,Hodgkin's disease, melanoma, multiple myeloma, chronic lymphocyticleukaemia and acute or chronic granulocytic lymphoma. The new productsaccording to the invention are especially useful for the treatment ofcancer of the ovary. The products according to the invention may be usedto prevent or delay the appearance or reappearance of the pathologicalconditions, or to treat these pathological conditions.

The products according to the invention may be administered to a patientaccording to different dosage forms suited to the chosen administrationroute, which is preferably the parenteral route. Parenteraladministration comprises intravenous, intraperitoneal, intramuscular orsubcutaneous administration. Intraperitoneal or intravenousadministration is more especially preferred.

The present invention also comprises pharmaceutical compositionscontaining at least one product of general formula (I), in a sufficientamount suitable for use in human or veterinary therapy. The compositionsmay be prepared according to the customary methods, using one or morepharmaceutically acceptable adjuvants, vehicles or excipients. Suitablevehicles include diluents, sterile aqueous media and various non-toxicsolvents. Preferably, the compositions take the form of aqueoussolutions or suspensions, injectable solutions which can containemulsifying agents, colourings, preservatives or stabilizers. However,the compositions may also be provided in the form of tablets, pills,powders or granules which can be administered via the oral route.

The choice of adjuvants or excipients may be determined by thesolubility and the chemical properties of the product, the particularmode of administration and good pharmaceutical practice.

For parenteral administration, sterile, aqueous or non-aqueous solutionsor suspensions are used. For the preparation of non-aqueous solutions orsuspensions, natural vegetable oils such as olive oil, sesame oil orliquid petroleum, or injectable organic esters such as ethyl oleate, maybe used. The sterile aqueous solutions can consist of a solution of apharmaceutically acceptable salt dissolved in water. The aqueoussolutions are suitable for intravenous administration provided the pH isappropriately adjusted and the solution is made isotonic, for examplewith a sufficient amount of sodium chloride or glucose. Thesterilization may be carried out by heating or by any other means whichdoes not adversely affect the composition.

It is clearly understood that all the products participating in thecompositions according to the invention must be pure and non-toxic inthe amounts used.

The compositions can contain at least 0.01% of therapeutically activeproduct. The amount of active product in a composition is such that asuitable dosage can be prescribed. Preferably, the compositions areprepared in such a way that a single dose contains from 0.01 to 1000 mgapproximately of active product for parenteral administration.

The therapeutic treatment may be performed concurrently with othertherapeutic treatments including antineoplastic drugs, monoclonalantibodies, immunotherapy or radiotherapy or biological responsemodifiers. The response modifiers include, without implied limitation,lymphokines and cytokines such as interleukins, interferons (α, β or δ)and TNF. Other chemotherapeutic agents which are useful in the treatmentof disorders due to abnormal cell proliferation include, without impliedlimitation, alkylating agents, for instance nitrogen mustards such asmechlorethamine, cyclophosphamide, melphalan and chlorambucil, alkylsulphonates such as busulfan, nitrosoureas such as carmustine,lomustine, semustine and streptozocin, triazenes such as dacarbazine,antimetabolites such as folic acid analogues, for instance methotrexate,pyrimidine analogues such as fluorouracil and cytarabine, purineanalogues such as mercaptopurine and thioguanine, natural products, forinstance vinca alkaloids such as vinblastine, vincristine and vindesine,epipodophyllotoxins such as etoposide and teniposide, antibiotics suchas dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin andmitomycin, enzymes such as L-asparaginase, various agents such ascoordination complexes of platinum, for instance cisplatin, substitutedureas such as hydroxyurea, methylhydrazine derivatives such asprocarbazine, adrenocortical suppressants such as mitotane andaminoglutethimide, hormones and antagonists such asadrenocorticosteroids such as prednisone, progestins such ashydroxyprogesterone caproate, methoxyprogesterone acetate and megestrolacetate, oestrogens such as diethylstilboestrol and ethynyloestradiol,antioestrogens such as tamoxifen, and androgens such as testosteronepropionate and fluoxymesterone.

The doses used for carrying out the methods according to the inventionare those which permit a prophylactic treatment or a maximum therapeuticresponse. The doses vary according to the administration form, theparticular product selected and the features distinctive to the subjectto be treated. In general, the doses are those which are therapeuticallyeffective for the treatment of disorders due to abnormal cellproliferation. The products according to the invention may beadministered as often as necessary to obtain the desired therapeuticeffect. Some patients may respond rapidly to relatively high or lowdoses, and then require low or zero maintenance doses. Generally, lowdoses will be used at the beginning of the treatment and, if necessary,increasingly stronger doses will be administered until an optimum effectis obtained. For other patients, it may be necessary to administermaintenance doses 1 to 8 times a day, and preferably 1 to 4 times,according to the physiological requirements of the patient in question.It is also possible that some patients may require the use of only oneto two daily administrations.

In man, the doses are generally between 0.01 and 200 mg/kg. Forintraperitoneal administration, the doses will generally be between 0.1and 100 mg/kg, preferably between 0.5 and 50 mg/kg and still morespecifically between 1 and 10 mg/kg. For intravenous administration, thedoses are generally between 0.1 and 50 mg/kg, preferably between 0.1 and5 mg/kg and still more specifically between 1 and 2 mg/kg. It isunderstood that, in order to choose the most suitable dosage, accountshould be taken of the administration route, the patient's weight,general state of health and age and all the factors which may influencethe efficacy of the treatment.

The example which follows illustrates a composition according to theinvention.

EXAMPLE

40 mg of the product obtained in Example 1 are dissolved in 1 cm³ ofEmulphor EL 620 and 1 cm³ of ethanol, and the solution is then dilutedby adding 18 cm³ of physiological saline.

The composition is administered by perfusion over 1 hour by introductionin physiological solution.

We claim:
 1. Taxoids of formula I: ##STR18## in which Z represents ahydrogen atom or a radical of general formula: ##STR19## in which: R₁represents a benzoyl radical optionally substituted with one or moreidentical or different atoms or radicals selected from halogen atoms,alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicalscontaining 1 to 4 carbon atoms, trifluoromethyl radicals, thenoyl orfuroyl radicals, or a radical R₂ --O--CO-- in which R₂ represents:analkyl radical containing 1 to 8 carbon atoms, an alkenyl radicalcontaining 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, acycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkylradical containing 7 to 10 carbon atoms, these radicals being optionallysubstituted with one or more substituents selected from halogen atoms,hydroxyl radicals, alkoxy radicals containing 1 to 4 carbon atoms,dialkylamino radicals in which each alkyl portion contains 1 to 4 carbonatoms, piperidino radicals, morpholino radicals, 1-piperazinyl radicals(optionally substituted at the 4-position with an alkyl radicalcontaining 1 to 4 carbon atoms or with a phenylalkyl radical in whichthe alkyl portion contains 1 to 4 carbon atoms), cycloalkyl radicalscontaining 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6carbon atoms, phenyl radicals (optionally substituted with one or moreatoms or radicals chosen from halogen atoms, alkyl radicals containing 1to 4 carbon atoms, or alkoxy radicals containing 1 to 4 carbon atoms),cyano or carboxyl radicals or alkoxycarbonyl radicals in which the alkylportion contains 1 to 4 carbon atoms, a phenyl or α- or β-naphthylradical optionally substituted with one or more atoms or radicalsselected from halogen atoms, alkyl radicals containing 1 to 4 carbonatoms, or alkoxy radicals containing 1 to 4 carbon atoms, or a5-membered aromatic heterocyclic radical, or a saturated heterocyclicradical containing 4 to 6 carbon atoms, optionally substituted with oneor more alkyl radicals containing 1 to 4 carbon atoms, R₃ represents anunbranched or branched alkyl radical containing 1 to 8 carbon atoms, anunbranched or branched alkenyl radical containing 2 to 8 carbon atoms,an unbranched or branched alkynyl radical containing 2 to 8 carbonatoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a phenyl orα- or β-naphthyl radical optionally substituted with one or more atomsor radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryl,aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl,mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino,amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl,alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethylradicals, or a 5-membered aromatic heterocycle containing one or moreidentical or different hetero atoms selected from nitrogen, oxygen andsulphur atoms and optionally substituted with one or more identical ordifferent substituents chosen from halogen atoms and alkyl, aryl, amino,alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylcarbonyl,cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl oralkoxycarbonyl radicals, wherein, in the substituents of the phenyl, α-or β-naphthyl and aromatic heterocyclic radicals, the alkyl radicals andthe alkyl portions of the other radicals contain 1 to 4 carbon atoms,and the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms, andthe aryl radicals are phenyl or α- or β-naphthyl radicals, R₄ representsa hydroxyl radical or an alkoxy radical containing 1 to 6 carbon atomsin an unbranched or branched chain, an alkenyloxy radical containing 3to 6 carbon atoms in an unbranched or branched chain, an alkynyloxyradical containing 3 to 6 carbon atoms in an unbranched or branchedchain, a cycloalkyloxy radical containing 3 to 6 carbon atoms, acycloalkenyloxy radical containing 3 to 6 carbon atoms, an alkanoyloxyradical in which the alkanoyl portion contains 3 to 6 carbon atoms in anunbranched or branched chain, an alkenoyloxy radical in which thealkenoyl portion contains 3 to 6 carbon atoms in an unbranched orbranched chain, an alkynoyloxy radical in which the alkynoyl portioncontains 3 to 6 carbon atoms in an unbranched or branched chain, analkoxyacetyl radical in which the alkyl portion contains 1 to 6 carbonatoms in an unbranched or branched chain, an alkylthioacetyl radical inwhich the alkyl portion contains 1 to 6 carbon atoms in an unbranched orbranched chain or an alkyloxycarbonyloxy radical in which the alkylportion contains 1 to 6 carbon atoms in an unbranched or branched chain,these radicals being optionally substituted with one or more halogenatoms, an alkoxy radical containing 1 to 4 carbon atoms, an alkylthioradical containing 1 to 4 carbon atoms or a carboxyl radical, analkyloxycarbonyl radical in which the alkyl portion contains 1 to 4carbon atoms, a cyano or carbamoyl radical or an N-alkylcarbamoyl orN,N-dialkylcarbamoyl radical in which each alkyl portion contains 1 to 4carbon atoms or, with the nitrogen atom to which it is linked, forms asaturated 5- or 6-membered heterocyclic radical optionally containing asecond hetero atom chosen from oxygen, sulphur and nitrogen atoms,optionally substituted with an alkyl radical containing 1 to 4 carbonatoms or a phenyl radical or a phenylalkyl radical in which the alkylportion contains 1 to 4 carbon atoms, or alternatively R₄ represents abenzoyloxy radical or a heterocyclylcarbonyloxy radical in which radicalthe heterocyclic portion represents a 5- or 6-membered aromaticheterocycle containing one or more hetero atoms selected from oxygen,sulphur and nitrogen atoms, R₅ represents an alkoxy radical containing 1to 6 carbon atoms in an unbranched or branched chain optionallysubstituted with an alkoxy radical containing 1 to 4 carbon atoms, analkenyloxy radical containing 3 to 6 carbon atoms, an alkynyloxy radicalcontaining 3 to 6 carbon atoms, a cycloalkyloxy radical containing 3 to6 carbon atoms, a cycloalkenyloxy radical containing 3 to 6 carbonatoms, these radicals being optionally substituted with one or morehalogen atoms, an alkoxy radical containing 1 to 4 carbon atoms, analkylthio radical containing 1 to 4 carbon atoms or a carboxyl radical,an alkyloxycarbonyl radical in which the alkyl portion contains 1 to 4carbon atoms, a cyano or carbamoyl radical or an N-alkylcarbamoyl orN,N-dialkylcarbamoyl radical in which each alkyl portion contains 1 to 4carbon atoms or, with the nitrogen atom to which it is linked, forms asaturated 5- or 6-membered heterocyclic radical optionally containing asecond hetero atom selected from oxygen, sulphur and nitrogen atoms,optionally substituted with an alkyl radical containing I to 4 carbonatoms or a phenyl radical or a phenylalkyl radical in which the alkylportion contains 1 to 4 carbon atoms.
 2. A taxoid according to claim 1,wherein Z represents a hydrogen atom or a radical of general formula(II) in whichR₁ represents a benzoyl radical or a radical R₂ --O--CO--in which R₂ represents a tert-butyl radical and R₃ represents an alkylradical containing 1 to 6 carbon atoms, an alkenyl radical containing 2to 6 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms,a phenyl radical optionally substituted with one or more identical ordifferent atoms or radicals selected from halogen atoms and alkyl,alkoxy, dialkylamino, acylamino, alkoxycarbonylamino and trifluoromethylradicals, or a 2- or 3-furyl, 2- or 3-thienyl or 2-, 4- or 5-thiazolylradical, and R₄ represents a hydroxyl radical or an unbranched orbranched alkyloxy radical containing 1 to 6 carbon atoms and R₅represents an unbranched or branched alkyloxy radical containing 1 to 6carbon atoms.
 3. A taxoid according to claim 1, wherein Z represents ahydrogen atom or a radical of general formula (II) in whichR₁ representsa benzoyl radical or a radical R₂ --O--CO-- in which R₂ represents atert-butyl radical and R₃ represents an isobutyl, isobutenyl, butenyl,cyclohexyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl,4-thiazolyl or 5-thiazolyl radical, R₄ represents a hydroxyl radical ora methoxy radical and R₅ represents a methoxy radical.
 4. A process forthe preparation of a taxoid according to claim 1, wherein Z represents aradical of general formula (II), said process comprising esterifying aproduct of general formula Ill: ##STR20## in which R₄ and R₅ are definedin claim 1 by means of an acid of general formula IV: ##STR21## in whichR₁ and R₃ are defined in claim 1 and either R₆ represents a hydrogenatom and R₇ represents a group protecting the hydroxyl function, or R₆and R₇ together form a saturated 5- or 6-membered heterocycle, or of aderivative of this acid, to obtain an ester of general formula V:##STR22## in which R₁, R₃, R₄, R₅, R₆ and R₇ are defined as above,andthe protective groups represented by R₇ and/or R₆ and R₇ are replacedwith hydrogen atoms and, optionally, the R₄ radical is replaced with ahydroxyl radical.
 5. The process according to claim 4, wherein theesterification is carried out by means of an acid of general formula(IV), in the presence of a condensing agent and of an activating agent,in an organic solvent at a temperature of between -10 and 90° C.
 6. Theprocess according to claim 4, wherein the esterification is carried outby means of an acid of general formula (IV) in the form of a symmetricanhydride, working in the presence of an activating agent, in an organicsolvent at a temperature of between 0 and 90° C.
 7. The processaccording to claim 4, wherein the esterification is carried out usingthe acid of general formula (IV) in the form of a halide or in the formof a mixed anhydride with an aliphatic or aromatic acid, optionallyprepared in situ, in the presence of a base, working in an organicsolvent at a temperature of between 0 and 80° C.
 8. The processaccording to claim 4, wherein the protective groups R₇ and/or R₆ and R₇are replaced with hydrogen atoms, according to their nature, in thefollowing manner:1) When R₆ represents a hydrogen atom and R₇ representsa group protecting the hydroxyl function, the replacement of theprotective groups with hydrogen atoms is carried out by means of aninorganic acid or an organic acid, used alone or in the form of amixture, working in an organic solvent chosen from alcohols, ethers,esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons,aromatic hydrocarbons and nitrites, at a temperature of between -10 and60° C., 2) When R₆ and R₇ together form a saturated 5- or 6-memberedheterocycle of general formula: ##STR23## in which R₁ is defined asabove, R₈ and R₉, which are identical or different, represent a hydrogenatom, an alkyl radical containing 1 to 4 carbon atoms, an aralkylradical in which the alkyl portion contains 1 to 4 carbon atoms and thearyl portion represents a phenyl radical optionally substituted with oneor more alkoxy radicals containing 1 to 4 carbon atoms, or an arylradical representing a phenyl radical optionally substituted with one ormore alkoxy radicals containing 1 to 4 carbon atoms, R₈ represents analkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radicalor a phenyl radical substituted with a trihalomethyl radical and R₉represents a hydrogen atom, orR₈ and R₉ together form, with the carbonatom to which they are linked, a ring having 4 to 7 members, thereplacement of the protective group formed by R₆ and R₇ with hydrogenatoms is carried out, according to the meanings of R₁, R₈ and R₉,working in the following manner:a) When R₁ represents atert-butoxycarbonyl radical, R₈ and R₉, which are identical ordifferent, represent an alkyl radical or an aralkyl or aryl radical,either R₈ represents a trihalomethyl radical or a phenyl radicalsubstituted with a trihalomethyl radical, and R₉ represents a hydrogenatom, or R₈ and R₉ together form a 4- to 7-membered ring, the ester ofgeneral formula (V) is treated with an inorganic or organic acid,optionally in an organic solvent such as an alcohol, to give the productof general formula VII: ##STR24## in which R₃, R₄ and R₅ are defined asabove, which is acylated by means of benzoyl chloride in which thephenyl ring is optionally substituted, thenoyl chloride, furoyl chlorideor a product of general formula VII:

    R.sub.2 --O--CO--X                                         (VIII)

in which R₂ is defined as above and X represents a halogen atom or aresidue --O--R₂ or --O--CO--O--R₂, to obtain a taxoid according to claim1 wherein Z represents a radical of general formula (II), b) When R₁represents an optionally substituted benzoyl radical, a thenoyl orfuroyl radical or a radical R₂ O--CO-- in which R₂ is defined as above,R₈ represents a hydrogen atom or an alkoxy radical containing 1 to 4carbon atoms or a phenyl radical substituted with one or more alkoxyradicals containing 1 to 4 carbon atoms and R₉ represents a hydrogenatom, the protective group formed by R₆ and R₇ is replaced with hydrogenatoms is carried out in the presence of an inorganic acid or an organicacid, used alone or in the form of a mixture, in a stoichiometric orcatalytic quantity, working in an organic solvent chosen from alcohols,ethers, esters, aliphatic hydrocarbons, halogenated aliphatichydrocarbons and aromatic hydrocarbons at a temperature of between -10and 60° C.
 9. A process for the preparation of a taxoid according toclaim 1, wherein Z represents a hydrogen atom or a radical of generalformula (II), wherein a product of general formula IX:

    R'.sub.4 --X.sub.1                                         (IX)

in which R'₄ is such that R'₄ --O is identical to R₄ defined in claim 1and X₁ represents a halogen atom, is reacted with a product of generalformula X: ##STR25## in which R₅ is defined as in claim 1 and Z₁represents a hydrogen atom, a group protecting the hydroxyl function ora radical of general formula XI: ##STR26## in which R₁ and R₃ aredefined as in claim 1, and R₆ represents a hydrogen atom and R₇represents a group protecting the hydroxyl function, or R₆ and R₇together form a saturated 5- or 6-membered heterocycle, and then theprotective groups represented or carried by Z₁ are optionally replacedunder the conditions described in claim
 8. 10. The process according toclaim 9, wherein the product of general formula (IX) is reacted with theproduct of general formula (X), after metalation of the hydroxylfunction at the 10-position by means of an alkali metal hydride, analkali metal amide or an alkali metal alkylide, working in an organicsolvent chosen from dimethylformamide or tetrahydrofuran, at atemperature of between 0 and 50° C. 11.4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,α-dihydroxy-7β-methoxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. 12.4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,10α-dimethoxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionite.
 13. Apharmaceutical composition comprising at least one taxoid according toclaim 1, wherein Z represents a radical of general formula (II), incombination with one or more pharmaceutically acceptable diluents oradjuvants and optionally one or more compatible and pharmacologicallyactive compounds.
 14. A pharmaceutical composition comprising at leastone compound according to claim 11 in combination with one or morepharmaceutically acceptable diluents or adjuvants and optionally one ormore compatible and pharmacologically active compounds.
 15. Apharmaceutical composition comprising at least one compound according toclaim 12 in combination with one or more pharmaceutically acceptablediluents or adjuvants and optionally one or more compatible andpharmacologically active compounds.
 16. The taxoid according to claim 1,wherein, in the definition of R₁, the 5-membered aromatic heterocyclicradical is a furyl or thienyl radical.
 17. The process according toclaim 4, wherein R₄ represents a group protecting the hydroxyl function.18. The process according to claim 17, wherein said group protecting thehydroxyl function is selected from alkoxyacetyl radicals.